RU2375345C1 - Method of producing 2,7-bis[2-(diethylamino)ethoxy]fluoren -9-one dihydrochloride (thylorone) - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: improved method of producing 2,7-bis[2-(diethylamino)ethoxy]fluoren-9-one dihydrochloride, known as thylorone or amixine, and used as an immunostimulating and antiviral agent, involves treating 2,7-bis[2-(diethylamino)ethoxy]fluoren-9-one in methylene chloride with hydrogen chloride in gaseous state of in form of hydrochloric acid, preferably in molar ratio 2,7-bis[2-(diethylamino)ethoxy]fluoren-9-one : hydrochloric acid equal to 1:2.05-3.0. A solution of 2,7-bis[2-(diethylamino)ethoxy]fluoren-9-one dihydrochloride in methylene chloride is obtained, which is cooled to temperature not below minus 12°C to obtain a suspension and then filtered and dried. The filtered residue is dried in inert gas or air at temperature from 90 to 110°C or in a vacuum, as a rule. Completion of salt formation is usually controlled from increase in temperature of the reaction mass and its stabilisation to a value between 32 and 34°C, as well as from the pH value, which must not be higher than 4.0. The filtered residue is dried in an inert gas or air, at temperature from 90 to 110°C or in a vacuum, as a rule.

EFFECT: simplification of the process due to exclusion of inflammable solvents and obtaining a product of high quality with high output.

6 cl, 1 dwg, 3 ex

Description

The invention relates to the field of organic chemistry and chemical technology, in particular to the chemical synthesis of 2,7-bis [2- (diethylamino) ethoxy] fluoren-9-one dihydrochloride of the formula I

drug substance Tiloron.

Tiloron (amiksin) is an inducer of endogenous interferon, which is used as an immunostimulating and antiviral agent.

A known method of producing salt is 2,7-bis [2- (diethylamino) ethoxy] fluoren-9-one dihydrochloride (SM Burke, M. Joullie. New Synthetic Pathways to Tilorone Hydrochloride. Synthetic Comm, 1976, v. 6 (5) , 371-376). In this method, the synthesized base - 2,7-bis [2- (diethylamino) ethoxy] fluoren-9-one, is dissolved in methanol in the last stage, followed by treatment of the resulting solution with dry hydrogen chloride in diethyl ether, which leads to the formation of 2,7- bis [2- (diethylamino) ethoxy] fluoren-9-one dihydrochloride. Then, the precipitate formed is crystallized from methanol: isopropanol mixture at a ratio of 1: 3 in the mixture. The output at the stage of 50%. The literature does not indicate that this method has been tested with industrial scaling technology.

The disadvantages of this method are the low yield and low quality of the final product, incompatible with the purity requirement for the pharmacopoeial product, the explosion and fire hazard of the last stage, the lack of industrial scaling technology.

It is known to use hydrogen chloride, which is pre-dissolved in ethanol (JP patent 9031036 dated 04.02.97), after which this solution is applied to a solution of 2,7-bis [2- (diethylamino) ethoxy] fluoren-9-one in isopropanol to obtain 2 , 7-bis [2- (diethylamino) ethoxy] fluoren-9-one dihydrochloride.

The disadvantage of this method is the fire hazard of the process and the possibility of industrial scaling of the process is not confirmed.

A known method of producing salt - 2,7-bis [2- (diethylamino) ethoxy] fluoren-9-one dihydrochloride (RU 2218327, C07C 225/18, 03/17/1999). In this method, the synthesized base in the last stage is dissolved in acetone and converted into a salt by the action of 35% hydrochloric acid, which is added to the acetone solution of the base -2,7-bis [2- (diethylamino) ethoxy] fluoren-9-one. The yield at this stage is 57%. In the examples of the patent it is indicated that this method has been tested with industrial scaling and is used in serial production of the drug substance "Amiksin" (Tiloron).

The disadvantages of this method are the low yield and explosion hazard of the last stage.

A known method of producing salt - 2,7-bis [2- (diethylamino) ethoxy] fluoren-9-one dihydrochloride (patent application RU2003121101, С07С 225/18, 07/14/2003), including preliminary stages for obtaining the base - 2,7- bis [2- (diethylamino) ethoxy] fluoren-9-one, in which 2,7-bis [2- (diethylamino)

ethoxy] fluoren-9-one dihydrochloride is obtained by exposure to a solution of 2,7-bis [2- (diethylamino) ethoxy] fluoren-9-one in acetone of dried gaseous hydrogen chloride.

The abstract of the application does not indicate that this method has been tested with industrial scaling technology.

This publication does not contain information about the output and quality of the final product. A significant disadvantage of this method is the explosion hazard at the last stage.

Closest to the proposed invention is a method for producing salt of 2,7-bis [2- (diethylamino) ethoxy] fluoren-9-one dihydrochloride (RU 2076097, С07С 225/18, 01/17/1994). In this method, the synthesized base in the form of an aqueous suspension is treated with a 20-25% hydrochloric acid solution, filtered, washed until neutral and dried to obtain the desired product - 2,7-bis [2- (diethylamino) ethoxy] fluoren-9- she dihydrochloride with a yield of 90% at this stage.

The patent does not indicate that when using this method, the same yield can be achieved with industrial scaling technology.

The disadvantage of this method is the insufficiently high yield and lack of industrial scaling technology.

The objective of the invention is to provide a method for producing 2,7-bis [2- (diethylamino) ethoxy] fluoren-9-one dihydrochloride (tilorone).

The technical result that can be obtained by using the present invention is to ensure a high yield of the final product - 2,7-bis [2- (diethylamino) ethoxy] fluoren-9-one dihydrochloride and, in addition, high purity of the final product with industrial scaling technologies, elimination of fire and explosion hazard.

To solve this problem, the present invention provides a method for producing 2,7-bis [2- (diethylamino) ethoxy] fluoren-9-one dihydrochloride, wherein 2,7-bis [2- (diethylamino) ethoxy] fluoren-9-one dissolved in methylene chloride, the resulting solution is treated with hydrogen chloride in the form of gaseous hydrogen chloride or hydrochloric acid solution, until the formation of salt. Then a solution of 2,7-bis [2- (diethylamino) ethoxy] fluoren-9-one dihydrochloride in methylene chloride is cooled to obtain a suspension and filtered, after which the filtered precipitate is dried.

The process of salt formation during the processing of a solution of 2,7-bis [2- (diethylamino) ethoxy] fluoren-9-one in methylene chloride with dry hydrogen chloride is controlled by increasing the temperature of the reaction mass to plus 32-34 ° С and its stabilization, and the completion of the stage is the pH of the aqueous extract of the reaction mass, which should be no more than 4.0.

When using hydrochloric acid in the process of salt formation, a calculated amount of hydrochloric acid is added to the solution of the base - 2,7-bis [2- (diethylamino) ethoxy] fluoren-9-one in methylene chloride, which ensures the complete conversion of the base to salt, in a molar ratio of 2.7 bis [2- (diethylamino) ethoxy] fluoren-9-one: hydrochloric acid 1: 2.05-3.0, then, after completion of the salt formation, azeotropic distillation of water is carried out.

The cooling of the salt solution of 2,7-bis [2- (diethylamino) ethoxy] fluoren-9-one dihydrochloride in methylene chloride is carried out to a temperature of at least minus 12 ° C.

When processing a solution of 2,7-bis [2- (diethylamino) ethoxy] fluoren-9-one in methylene chloride, preferably dry gaseous hydrogen chloride is used.

The filtered precipitate is dried at a temperature of + 90-110 ° C in an inert gas or air, or in vacuum.

When vacuum drying the product, it is preferred that the drying is carried out at a residual pressure of not higher than 10 mm Hg. with periodic mixing of the product.

The duration of the drying process in an inert gas or air is 22 - 26 hours, in a vacuum of 6-9 hours.

Thus, high-quality 2,7-bis [2- (diethylamino) ethoxy] fluoren-9-one dihydrochloride (pharmacopoeial substance Tiloron) is obtained with a yield of 90.4-95.0%, calculated on the basis of 2.7- bis [2- (diethylamino) ethoxy] fluoren-9-one.

Methylene chloride separated from 2,7-bis [2- (diethylamino) ethoxy] fluoren-9-one dihydrochloride is sent for regeneration in order to reuse the purified methylene chloride in the process.

The possibility of carrying out the invention is illustrated by the following examples of the synthesis of 2,7-bis [2- (diethylamino) ethoxy] fluoren-9-one dihydrochloride - the drug substance Tiloron.

Example 1

150 l of methylene chloride are pumped into a 200 l reactor. The stirrer in the reactor is turned on and 15 kg of the base, 2,7-bis [2- (diethylamino) ethoxy] fluoren-9-one, are loaded into it. Mix the contents of the reactor for 30 minutes until the base is dissolved. Hydrogen chloride gas is fed into the resulting solution. The supply of dry gaseous hydrogen chloride to the salt production reactor is continued until the temperature of the reaction mixture ceases to increase (32-34 ° C). A sample is then taken from the reactor to determine the pH value. In this case, the selected sample (100 ml) is treated in a separatory funnel with an equal volume of distilled water, methylene chloride is separated and the pH of the aqueous layer is measured. If the pH is less than 4.0, the flow of gaseous hydrogen chloride is stopped. If the pH value is greater than 4.0, then the supply of gaseous hydrogen chloride is resumed and continued until the pH of the aqueous extract of the solution in the reactor is 4.0.

After completion of the salt formation process, the mass is cooled in the reactor to a temperature of 20-25 ° C, at which crystallization of 2,7-bis [2- (diethylamino) ethoxy] fluoren-9-one dihydrochloride begins. Then cool the mass in the reactor to a temperature of minus 10-12 ° C, at which the crystallization of the salt is completed. The precipitate obtained is filtered on a Druk filter and dried for 24 hours in a shelf dryer in air with periodic product stirring. After drying, grinding and sieving, 15.5 kg of the finished product are obtained (yield 90.4%). T. pl. 234-235 ° C (Kofler's stand).

Example 2

80 kg of 2,7-bis [2- (diethylamino) ethoxy] fluoren-9-one are loaded into a single-cube apparatus and 800 l of methylene chloride are poured. Stir until the base is completely dissolved. The supply of dry gaseous hydrogen chloride to the salt synthesis reactor is continued until the temperature of the reaction mixture ceases to increase (32-34 ° C). Hydrogen chloride is fed into the resulting solution until the pH of the aqueous extract is 4.0.

Then the reaction mass is cooled to plus 5 ° C. The resulting suspension is filtered under vacuum on a suction filter. The resulting 2,7-bis [2- (diethylamino) ethoxy] fluoren-9-one dihydrochloride is dried in a shelf dryer in nitrogen atmosphere for 24 hours at a temperature of 90-110 ° C with periodic stirring.

After drying, grinding and sieving, 88.4 kg of the finished product are obtained (yield 93.5%). T. pl. 234-235 ° C (Kofler's stand).

Example 3

In 200 l of the reactor, 8.2 kg of 2,7-bis [2- (diethylamino) ethoxy] fluoren-9-one are poured and 140 l of methylene chloride are poured. Stir until the base is completely dissolved. 5.2 l of concentrated hydrochloric acid is added to the solution with stirring. After completion of salt formation, water is azeotropically distilled off from a solution of 2,7-bis [2- (diethylamino) ethoxy] fluoren-9-one dihydrochloride in methylene chloride. After distillation of water, the solution is cooled to a temperature of 10-12 ° C.

The resulting suspension was filtered under vacuum, the precipitate was washed with methylene chloride cooled to 5 ° C. The resulting 2,7-bis [2- (diethylamino) ethoxy] fluoren-9-one dihydrochloride is dried in a vacuum dryer for 6 hours at a residual pressure of 10 mm Hg. and a temperature of 90-110 ° C.

After drying, grinding and sieving, 9.19 kg are obtained (95.2% yield). T. decomp. 234.5-235.5 ° C (Kofler's stand).

Chromatography of samples of 2,7-bis [2- (diethylamino) ethoxy] fluoren-9-one dihydrochloride was carried out under the following conditions: Merck plate, benzene: triethanolamine: methanol solvent system for chromatography 100: 10: 1. Detection in UV light (254 nm).

The drawing shows a thin layer chromatogram (TLC) of the standard and the sample obtained according to Example 1 (1-0.05 μg of 2,7-bis [2- (diethylamino) ethoxy] fluoren-9-one dihydrochloride - intensity standard for determining impurities 0, 1%; 2-50 μg of the sample obtained according to Example 1; 3-100 μg of the same sample).

It is seen that in the sample obtained according to Example 1, there are no impurities comprising more than 0.1%.

The samples of Examples 2 and 3 are identical to the sample of Example 1 according to the results of analysis of thin layer chromatography.

A method for producing 2,7-bis [2- (diethylamino) ethoxy] fluoren-9-one dihydrochloride is proposed, which provides a high yield of the finished product while ensuring its pharmacopoeial purity using non-combustible cheap methylene chloride, as well as dry gaseous hydrogen chloride or hydrochloric acid with subsequent azeotropic distillation of water.

The presence on the market of Russian products of only one industrial domestic producer (ZAO Biological Research and Systems) and one foreign (OAO Interchem, Ukraine) 2,7-bis [2- (diethylamino) ethoxy] fluoren-9-one pharmacopeia dihydrochloride quality indicates the complexity of scaling the technological process of production of this product. Moreover, according to the regulatory documentation of a foreign manufacturer (ND 42-100050-), two foreign impurities are allowed in the pharmaceutical substance “Amiksin” (Tiloron) manufactured by him.

In the drug substance Tiloron, the release of which according to the proposed invention is industrially tested by the applicant, there are no foreign impurities.

Thus, the quality of the pharmaceutical substance Tiloron according to the method proposed in the application, taking into account industrial scaling, is higher than the quality of the pharmaceutical substance Amiksin (Tiloron), industrially produced by a foreign manufacturer.

In the proposed method, the action on a solution of 2,7-bis [2- (diethylamino) ethoxy] fluoren-9-one in methylene chloride of gaseous hydrogen chloride or hydrochloric acid provides a higher yield of the final product - 2,7-bis [2- (diethylamino) ethoxy] fluoren-9-one dihydrochloride (90.4-95.2%, instead of 90% of the analogue), as well as its high quality with industrial scaling, which was proved by the production of pilot industrial series of the drug substance Tiloron (1 spot instead of 3 according to the results of TLC), as well as the reduction of fire and explosion hazard due to the use of I am in the industrial production of the target product of a cheap widespread solvent - methylene chloride (instead of diethyl ether, methanol, acetone, isopropanol).

The search for information did not reveal identical and similar technical solutions.

The technical result of the method with exposure to a solution of 2,7-bis [2- (diethylamino) ethoxy] fluoren-9-one in methylene chloride with gaseous hydrogen chloride or hydrochloric acid does not follow explicitly from the prior art. Methylene chloride does not belong to any of the groups of compounds to which the previously used solvents for salt formation belong. Therefore, the claimed method has an inventive step.

The proposed method is currently tested in experimental conditions upon receipt of the experimental series of 2,7-bis [2- (diethylamino) ethoxy] fluoren-9-one dihydrochloride in the form of a drug substance Tiloron in an amount of from 9 to 92 kg, which indicates industrial applicability of the proposed method.

Claims (6)

1. The method of producing 2,7-bis [2- (diethylamino) ethoxy] fluoren-9-one dihydrochloride by treating 2,7-bis [2- (diethylamino) ethoxy] fluoren-9-one in a solvent with hydrogen chloride, followed by filtration and drying, characterized in that methylene chloride is used as a solvent, hydrogen chloride is used in gaseous form or in the form of hydrochloric acid to obtain a solution of 2,7-bis [2- (diethylamino) ethoxy] fluoren-9-one dihydrochloride in methylene chloride, which before filtering, cool to a temperature not lower than minus 12 ° C to obtain a suspension and. 2. The method according to claim 1, characterized in that when processing a solution of 2,7-bis [2- (diethylamino) ethoxy] fluoren-9-one in methylene chloride with gaseous hydrogen chloride, the completion of salt formation is controlled by increasing the temperature of the reaction mass and stabilizing it to values 32-34 ° C, as well as the pH value, which should be no more than 4.0. 3. The method according to claim 1, characterized in that the treatment of a solution of 2,7-bis [2- (diethylamino) ethoxy] fluoren-9-one in methylene chloride is carried out with hydrochloric acid in a molar ratio of 2,7-bis [2- (diethylamino ) ethoxy] fluoren-9-one: hydrochloric acid, equal to 1: 2.05-3.0, and after completion of salt formation, water is azeotropically distilled off. 4. The method according to claim 1, characterized in that when processing a solution of 2,7-bis [2- (diethylamino) ethoxy] fluoren-9-one in methylene chloride, dry gaseous hydrogen chloride is preferably used. 5. The method according to claim 1, characterized in that the filtered precipitate is dried in an inert gas or air in vacuum at a temperature of 90-110 ° C. 6. The method according to claim 1, characterized in that the filtered precipitate is dried in vacuum.

Images